DVT: A New Era in Anticoagulant Therapy DVT: A New Era in Anticoagulant Therapy

Thrombosis is the leading cause of morbidity and mortality in the Western world. Arterial thrombosis leads to myocardial infarction and stroke. Arterial clots are platelet-rich and fibrin-poor (so-called white clots). They are generated at sites of vascular injury under high shear rates and are prevented or treated with antiplatelet drugs.1 However, because of the fact that the thrombin is a potent activator of platelets and that arterial clots contain fibrin, anticoagulant drugs are also used to prevent arterial thrombosis. Venous thromboembolism (VTE), which includes deep vein thrombosis and pulmonary embolism, is the third leading cause of death after myocardial infarction and stroke. It is estimated that 2 million people have deep vein thrombosis in the United States, and of these 600 000 have a pulmonary embolism (one-third of which are fatal).2 Venous clots are fibrin-rich and platelet-poor (socalled red clots) because of the incorporation of red cells and low levels of platelets. They are prevented or treated with anticoagulant drugs.1 There are 3 major groups of patients that are administered anticoagulant drugs to treat or prevent venous thrombosis: (1) patients with VTE, who have had VTE, or are at risk for VTE, such as patients undergoing hip and knee replacement surgery; (2) patients at risk for stroke because of atrial fibrillation; and (3) acute coronary syndrome patients. Before discussing the anticoagulant drugs that are available to treat thrombosis, we will briefly summarize the coagulation protease cascade. Our knowledge of the cascade is based on many years of biochemical studies, the phenotype of patients with defects in the system, and, more recently, on knockout studies in mice. Rapid formation of a clot is required to limit bleeding after vascular injury. Because this cascade is essential for hemostasis, the major side effect of overdosing with an anticoagulant drug is bleeding. Patients with deficiencies in either factor VIII (hemophilia A) or factor IX (hemophilia B) have mild to severe bleeding, depending on the extent of the deficiency. Studies with mice have shown that an absence of components of the extrinsic pathway (tissue factor and factor VII) or the common pathway (factor V, factor X, and prothrombin) is not compatible with survival.3 In contrast, mice lacking components of the intrinsic pathway (factor VIII, factor IX, factor XI, and factor XII) survive. Factor VIII / and factor IX / mice have excessive bleeding after hemostatic challenge, whereas factor XI / and factor XII / mice have no hemostatic defects but are protected in thrombosis models.4 The coagulation cascade can be divided into 2 phases: initiation and propagation (Figure). The extrinsic pathway (tissue factor–factor VIIa) initiates the clotting cascade by activation of factor X and, to a lesser extent, factor IX, which leads to the generation of small amounts of thrombin because of the absence of the cofactors factor V and VIII. However, the tissue factor–factor VIIa is rapidly inactivated in a factor Xa-dependent manner by tissue factor pathway inhibitor. The small amount of thrombin generated in the first phase then initiates the propagation phase by activating the cofactors factor V and factor VIII, as well as factor XI and factor XIII. A recent study showed that polyphosphate released by platelets activates factor XII, thus providing an alternative route for activation of factor XI5 (Figure). The propagation phase is mediated by the intrinsic pathway, particularly the tenase complex (factor VIIIa–factor IXa), and this results in the generation of large amounts of thrombin and fibrin formation. The cell-based model of thrombosis proposes that platelets are the major thrombogenic surface for the propagation phase.6 Thrombin also activates platelets by cleavage of protease activated receptors.7 Vitamin K antagonists, such as warfarin, and unfractionated heparin have been the mainstay of anticoagulant therapy for 50 years. Vitamin K antagonists are oral drugs that interfere with a posttranslational modification of several coagulation proteins (factor VII, factor IX, factor X, and thrombin) and anticoagulant proteins (protein C and protein S) that is required for functional activity. The broad range of targets may be viewed as a disadvantage of these drugs. Initiation of vitamin K antagonist therapy requires short-term coverage with heparin because of a slow onset of action. Although vitamin K antagonist therapy is inexpensive, there are several problems, including a poor pharmacokinetics, a narrow therapeutic index, and numerous drug and dietary interactions. This means that long-term monitoring is required, which is expensive and inconvenient to the patient. Unfractionated heparin has a rapid onset of action but must be delivered intravenously or parenterally. Unfractionated heparin binds to antithrombin and enhances its ability to inactivate factor Xa and thrombin. A major side effect of unfracFrom Department of Medicine (N.M.), McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC; Duke University School of Medicine (R.C.B.), Duke Clinical Research Institute, Durham, NC. Correspondence to Nigel Mackman, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599. E-mail [email protected] (Arterioscler Thromb Vasc Biol. 2010;30:369-371.) © 2010 American Heart Association, Inc.